It has been known that, in organisms such as typically mammals, histamine that is a physiologically-active endogenous factor functions as a neurotransmitter and has extensive pharmacological activities (for example, see Life Science, Vol. 17, p. 503 (1975)).
Immunohistochemical studies have made it clear that a histamine-agonistic (producing) cell body exists in the nodal papillary nucleus in a posterior hypothalamic region and that histamine nerve fibers project in an extremely broad range in the brain, which supports various pharmacological effects of histamine (for example, see Journal of Comprehensive Neurology, Vol. 273, p. 283).
The existence of histamine-agonistic nerves in the nodal papillary nucleus in a posterior hypothalamic region suggests that histamine may have an important role in control of physiological functions relating to brain functions, especially to hypothalamic functions (sleep, vigilance rhythm, incretion, eating and drinking action, sexual action et al) (for example, see Progress in Neurobiology, Vol. 63, p. 637 (2001)).
The existence of the projection to the brain region that relates to vigilance sustenance, for example, to cerebral cortex, suggests the role in control of vigilance or vigilance-sleep cycle. The existence of the projection to many peripheral structures such as hippocampus and amygdaloid complex suggests the role in control of autonomic nerves, emotion, control of motivated action and learning/memory process.
When released from producing cells, histamine acts with a specific polymer that is referred to as a receptor on the surface of a cell membrane or inside a target cell, therefore exhibiting its pharmacological effects for control of various body functions. Heretofore, four types of histamine receptors have been found. In particular, the presence of a histamine receptor that participates in the central and peripheral nervous functions, a histamine-H3 receptor, has been shown by various pharmacological and physiological studies (for example, see Trends in Pharmacological Science, Vol. 8, p. 24 (1986)). Recently, human and rodent histamine-H3 receptor genes have been identified and their existence has been revealed (for example, see Molecular Pharmacology, Vol. 55, p. 1101 (1999)).
It is shown that a histamine-H3 receptor exists in the presynaptic membrane of central or peripheral neurocytes and functions as a self-receptor, therefore controlling the release of histamine and controlling even the release of other neurotransmitters. Specifically, it is reported that a histamine-H3 receptor agonist, or its antagonist or inverse-agonist controls the release of histamine, noradrenaline, serotonin, acetylcholine or dopamine from nerve terminal. For example, the release of these neurotransmitters is inhibited by an agonist such as (R)-(α)-methylhistamine, and is promoted by an antagonist or inverse-agonist such as thioperamide (for example, see Trends in Pharmacological Science, Vol. 19, p. 177 (1998)).
Recent studies have shown that a histamine-H3 receptor has extremely high homeostatic activities (activities observed in the absence of an endogenous agonistic factor, e.g., histamine) in the receptor-expressing cells/tissues or in a membrane fraction derived from the expressing cells/tissues and even in living bodies (for example, see Nature, Vol. 408, p. 860).
It is reported that these homeostatic activities are inhibited by an inverse-agonist. For example, thioperamide or syproxyfan inhibits the homeostatic self-receptor activity, and, as a result, promotes the release of neurotransmitters, for example, release and liberation of histamine from nerve terminal.
Regarding rats, a high-level selective inhibitor of histamine synthase (histidine decarboxylase) inhibits the vigilance of rats, and therefore it is shown that histamine participates in controlling motive vigilance. Regarding cats, administration of a histamine-H3 receptor agonist, (R)-(α)-methylhistamine to cats increases their deep slow-wave sleep (for example, see Brain Research, Vol. 523, p. 325 (1990)).
Contrary to this, a histamine-H3 receptor antagonist or inverse-agonist, thioperamide dose-dependently increases vigilance. In addition, thioperamide decreases slow-wave and REM sleep (see Life Science, Vol. 48, p. 2397 (1991)).
A histamine-H3 receptor antagonist or inverse-agonist, thioperamide or GT-2331 reduces emotional cataplexy and sleep of narcoleptic dogs (for example, see Brain Research, Vol. 793, p. 279 (1998)).
These informations suggest that the H3 receptor may participate in control of vigilance-sleep and in sleep disorder-associated diseases, further suggesting a possibility that a selective histamine-H3 agonist, antagonist or inverse-agonist may be useful for treatment of sleep disorders or various sleep disorder-associated diseases (for example, idiopathic hypersomnia, repetitive hypersomnia, true hypersomnia, narcolepsy, sleep periodic acromotion disorder, sleep apnea syndrome, circadian rhythm disorder, chronic fatigue syndrome, REM sleep disorder, senile insomnia, night workers' sleep insanitation, idiopathic insomnia, repetitive insomnia, true insomnia, depression, schizophrenia).
In animal experiments with rats, the administration of a histamine-H3 receptor antagonist or inverse-agonist, thioperamide or GT-2331 relieves the condition of learning disorder (LD) and attention deficit hyperactivity disorder (ADHD) (for example, see Life Science, Vol. 69, p. 469 (2001)). These informations suggest a possibility that the selective H3 agonist, antagonist or inverse-agonist may be useful for treatment and/or prevention of learning disorder or attention deficit hyperactivity disorder.
In animal experiments with rats, administration of histamine to their ventricle inhibits their eating action, therefore suggesting that histamine may participate in control of eating action (for example, see Journal of Physiology and Pharmacology, Vol. 49, p. 191 (1998)).
A histamine-H3 receptor antagonist or inverse-agonist, thioperamide dose-dependently inhibits eating action. In addition, thioperamide promotes intracerebral histamine release (for example, see Behavioral Brain Research, Vol. 104, p. 147 (1999)).
These informations suggest that a histamine H3 receptor may participate in eating action control, further suggesting that a histamine-H3 antagonist or inverse-agonist may be useful for prevention or remedy of metabolic system diseases such as eating disorder, obesity, diabetes, emaciation, hyperlipemia.
In animal experiments with rats, a histamine-H3 receptor agonist, (R)-(α)-methylhistamine dose-dependently lowers their basal diastolic pressure, and its action is antagonized by a histamine-H3 receptor antagonist or inverse-agonist, thioperamide (for example, see European Journal of Pharmacology, Vol. 234, p. 129, (1993)).
These informations suggest that a histamine-H3 receptor may participate in control of blood pressure, heart beat and cardiac output, further suggesting that a histamine-H3 receptor agonist, antagonist or inverse-agonist may be useful for prevention or remedy of circulatory system diseases such as hypertension and various cardiac disorders.
In animal experiments with rats, administration of a histamine-H3 receptor agonist, (R)-(α)-methylhistamine lowers their object cognitive and learning effects in the object cognition test and the passive turnout test with them. On the other hand, in a scopolamine-induced amnesia test, a histamine-H3 receptor antagonist or inverse-agonist, thioperamide dose-dependently relieves amnesia induced by the chemical (for example, see Pharmacology, Biochemistry and Behavior, Vol. 68, p. 735 (2001)).
These informations suggest a possibility that a histamine-H3 receptor antagonist or inverse-agonist may be useful for prevention or remedy of various diseases accompanied by memory/learning disorder, for example, Alzheimer's disease, Parkinson's disease or attention deficit/hyperactivity disorder.
In animal experiments with mice, a histamine-H3 receptor antagonist or inverse-agonist, thioperamide dose-dependently inhibits the spasm induced by electric shock or the epileptoid seizure induced by pentylene tetrazole (PTZ) (for example, see European Journal of Pharmacology, Vol. 234, p. 129 (1993), and Pharmacology, Biochemistry and Behavior, Vol. 68, p. 735 (2001)).
These informations suggest that a histamine-H3 receptor antagonist or inverse-agonist may be useful for prevention or remedy of epilepsy or central spasm.
As compounds structurally similar to those of formula (I) of the invention, for example, a compound of the following formula (A) is used as a production intermediate for β-carboline (see Bioorganic & Medicinal Chemistry Letters, Vol. 13, pp. 761-765, 2003):

The reference describes only the usability of the compound of formula (A) as a production intermediate for β-carboline, but this has neither description nor suggestion indicating that the compound may have a histamine-H3 receptor antagonistic effect or inverse-agonistic effect.
The reference says that the use of the β-carboline compounds that are produced via the compound of formula (A) as their production intermediate is for a phosphodiesterase-5 (PDE5) inhibitor, and this has neither description nor suggestion indicating that the compounds may have a histamine-H3 receptor antagonistic effect or inverse-agonistic effect.